盐酸戊乙奎醚预处理对婴幼儿体外循环后呼吸循环保护研究
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摘要
研究背景：小儿先天性心脏病(congenital heart diseases, CHD)手术疗效的提高不仅取决于临床手术技术的提高,对于围术期高危人群相关危险因素的分析以及采取相应的干预措施也是非常重要的。其中小儿体外循环(cardiopulmonary bypass, CPB)后呼吸循环功能障碍是导致小儿心内直视手术成功与否的关键因素。如何防止或减轻小儿CPB后心肺功能损伤是一项很重要的课题,也是引起心脏外科、麻醉科、体外循环科甚至术后ICU高度重视问题之一。围术期采用合理的药物干预措施,对于预防或减轻小儿CPB后呼吸、循环并发症具有重要意义。
CPB是把双刃剑,一方面可以帮助外科医生完成心脏外科手术,另一方面由于CPB中低温、血液稀释、非搏动灌注等非生理因素的影响,血液与异物表面接触,激活凝血系统、纤溶系统和白细胞,从而导致肠道、血管等组织器官通透性改变,产生内毒素血症和机体发生炎性反应。其中呼吸、循环是最易受累的重要系统。
大量离体和在体动物实验及临床研究都证实莨菪类药物具有改善微循环,细胞保护和抗再灌注损伤等作用。莨菪类药物的细胞保护作用,可能与阻断钙离子内流,抑制细胞膜的脂质过氧化有关。研究证实山莨菪碱有一定的器官保护作用,但因山莨菪碱副作用大,限制了其在临床的应用。盐酸戊乙奎醚(penehyclidine hydrochloride, PHC)是我国自主研究的新型长效胆碱能受体阻滞药。主要作用机制为选择性阻断中枢和外周的M1、M3和N1、N2受体,具有细胞保护作用,提高细胞对缺血缺氧的耐受性,稳定溶酶体和线粒体等亚细胞膜结构,减少溶酶体酶的释放,抑制花生四烯酸代谢产物的产生和休克因子的形成,减少毛细血管壁的通透性,减少炎性因子的渗出,持久的中枢镇静以及改善微循环的作用。已经广泛应用于临床。目前PHC对小儿CPB后呼吸、循环保护作用及机制相关报道甚少,本研究对比观察PHC预处理是否对婴幼儿CPB后呼吸循环功能具有保护作用及可能的作用机制,为临床婴幼儿CPB后重要脏器保护提供合适药物、剂量及理论依据。首先通过PHC应用于大样本小儿腹部手术麻醉前用药,观察与阿托品比较,不同剂量PHC在小儿腹部外科手术麻醉过程中的作用,为PHC预处理应用于内毒素诱导大鼠急性肺损伤模型和婴幼儿心内直视手术剂量选择提供依据；应用RT-PCR等技术对比观察PHC对内毒素诱导大鼠急性肺损伤的肺保护作用,为PHC预处理应用于婴幼儿心内直视手术呼吸功能保护提供实验和理论依据；最后选择不同剂量PHC预处理,观察婴幼儿CHD CPB后细胞因子、肺呼吸功能参数、血流动力学、应激反应和心肌损伤的变化,探讨PHC预处理对婴幼儿CPB后呼吸循环保护作用。
研究目的：探讨盐酸戊乙奎醚预处理对婴幼儿体外循环后呼吸循环保护作用。
材料与方法：
第一部分盐酸戊乙奎醚应用于小儿外科麻醉前用药临床研究
1535例小儿腹部手术(2008年1月～2009年12月,郑州大学第一附属医院小儿外科),随机分为三组：A组：静脉注射阿托品0.01mg/kg198例；P1组：静脉注射PHC0.02mg/kg608例；P2组：静脉注射PHC0.04mg/kg729例。所有小儿入诱导间外周静脉注射试验药物,30分钟后静脉注射氯胺酮2mg/kg,待患儿入睡后转入手术间,静脉复合全身麻醉,对比观察三组麻醉前用药唾液分泌量、体温和血流动力学变化。
第二部分盐酸戊乙奎醚对大鼠急性肺损伤修复的实验研究
48例清洁级健康成年雄性SD大鼠(郑州大学实验动物中心),随机分为4组：C组：尾静脉注射生理盐水1 ml/kg;M组：尾静脉注射大肠杆菌脂多糖(Lipopolysacharide,LPS)5mg/kg; P1组：尾静脉注射大肠杆菌LPS5mg/kg+PHC 0.25mg/kg;P2组：尾静脉注射大肠杆菌LPS5mg/kg+PHC0.75mg/kgo每组12只。将RT-PCR等方法应用于动物实验,建立内毒素诱导大鼠ALI模型,与对照组和模型组比较,观察血浆TNF-a和IL-6、血气、肺含水量、湿／干重比值(W/D)、CD14mRNA灰度比值、光镜和电镜结果。
第三部分本部分共分为两节
第一节盐酸戊乙奎醚预处理对婴幼儿体外循环后呼吸功能保护研究
第二节盐酸戊乙奎醚预处理对婴幼儿体外循环后循环功能保护研究
65例CHD手术(郑州大学第一附属医院心脏外科),随机分为三组：P1组：静脉注射PHC0.04mg·kg-125例；P2组：静脉注射PHC0.08mg·kg-129例；C组：同一时点静脉注射等容量生理盐水11例。颈内静脉穿刺成功后自右颈内静脉缓慢注入。年龄范围：8月～35月。男37例,女28例。体重6-16kg。所有患儿心功能Ⅱ-Ⅲ级,术前无肝肾功能及凝血功能异常,无肺动脉重度高压。射血分数(EF)≥60mmHg。各时点抽取左侧桡动脉血4ml,肝素抗凝。lml用于监测血气分析,3ml立即在4℃下以3000r/min离心10min,取上层血浆,置入-80℃冰箱内保存待测。各时点记录气道峰压。与常规组比较,观察不同剂量PHC血流动力学、Cd、RI、OI、Pmax、TNF-α、IL-6皮质醇、乳酸、血糖、cTn-Ⅰ、CK-MB结果。
所有数据应用SPSS17.0统计软件包进行统计学处理,计量资料以均数±标准差(x±s)表示,组内及组间比较采用方差分析,结果有差异后,采用LSD法进行两两比较,CPB前后比较采用配对t检验,计数资料采用x2检验,等级资料比较采用非参数检验,以a=0.05为显著性检验水准。
结果：
第一部分：
1.各组间性别、年龄、体重、麻醉时间(入诱导间至出苏醒室时间)、手术时间和苏醒时间(手术结束至出苏醒室时间)差异无统计学意义(P>0.05)。
2.唾液分泌物量的分级构成比较：采用非参数检验进行组间比较,两两比较采用Mann-Whitney检验,由于组间要进行3次两两比较,故对α进行校正,α'=0.05/3=0.0167。气管插管时,各组分泌物量差异有统计学意义(x 2=3342.76,P<0.01),A组和P1组比较有差异(Z=46.26,P<0.01),A组和P2组比较无差异(Z=2.25,P=-0.025>0.0167),P1组与P2组之间有统计学意义(Z=47.98,P<0.01)；气管拔管时,组间有统计学意义(x 2=3607.57,P<0.01),A组和P1组比较有差异(Z=37.64,P<0.01),A组和P2组比较有差异(Z=52.12,P<0.01),P1组与P2组之间有统计学意义(Z=47.07,P<0.01)。
3.体温比较：三组体温差异有统计学意义(x2=3407.82,P<0.05),基础体温差异无统计学意义(P＞0.05),组内比较,阿托品组在用药后30min升高,(P<0.05)。与A组比较,P1组、P2组在T1时点降低(P<0.05)
4.心率(HR)、平均动脉压(MAP)比较：
HR：三组HR差异有统计学意义(x 2=3278.17,P<0.05),基础HR差异无统计学意义(P>0.05)。与基础HR比较,阿托品组在用药后5 min,30min,60min明显上升(P<0.01)；PHC低剂量和高剂量组比较无差异(P＞0.05)。与阿托品组比较,PHC低剂量和高剂量组在用药后5 min,30min,60min明显下降(P<0.01)。PHC低剂量和高剂量组比较无差异(P>0.05)。
MAP：三组MAP比较无差异(x 2=263.19,P>0.05)。
第二部分：
1.四组血浆TNF-α比较：与对照组比较,模型组、PHC低剂量和高剂量组显著升高(P<0.01)；与模型组比较,PHC低剂量和高剂量组显著降低(P<0.01)；与低剂量组比较,高剂量组降低(P<0.05)。
2.四组血浆IL-6比较：与对照组比较,模型组、PHC低剂量和高剂量组显著升高(P<0.01)；与模型组比较,PHC低剂量和高剂量组显著降低(P<0.01)；与低剂量组比较,高剂量组降低(P<0.05)。
3.四组PaO2、PaCO2比较：
PaO2与对照组比较,模型组、PHC低剂量和高剂量组显著降低(P<0.01)；与模型组比较,PHC低剂量和高剂量组显著升高(P<0.01)；与低剂量组比较,高剂量组无差异(P>0.05)。
PaCO2与对照组比较,模型组升高(P<0.01)；与模型组比较,PHC低剂量和高剂量组降低(P<0.05),与低剂量组比较,高剂量组无差异(P>0.05)。
4.四组大鼠肺含水量比较：与对照组比较,模型组、PHC低剂量和高剂量组升高(P<0.05)；与模型组比较,PHC低剂量和高剂量组降低(P<0.05)；与低剂量组比较,高剂量组无差异(P>0.05)。
5.四组湿/干重比值(W/D)比较：与对照组比较,模型组、PHC低剂量和高剂量组升高(P<0.05)；与模型组比较,PHC低剂量和高剂量组降低(P<0.05)；与低剂量组比较,高剂量组无差异(P>0.05)。
6.四组大鼠CD14mRNA灰度比值(A值)：与正常对照组比较,模型组、低剂量组和高剂量组升高(P<0.05)；与模型组组比较,低剂量组和高剂量组降低(P<0.05),与低剂量组比较,高剂量组降低(P<0.05)。
7.肺组织病理改变光镜结果(200×)
对照组为正常大鼠肺组织,肺泡结构清晰,肺泡壁薄,未见炎性细胞浸润；模型组肺组织高度水肿、出血,肺间质增宽,肺泡腔和肺间质内可见大量红细胞,肺泡明显萎陷,炎症细胞大量浸润,肺泡完整性破坏；低剂量组肺组织水肿,肺间质增宽不明显,肺泡萎陷减轻,少量炎性细胞浸润,肺泡结构较完整；高剂量组肺组织轻度水肿,见炎性细胞浸润,肺泡结构完整。
8.肺微血管内皮细胞及基底膜形态电镜结果(6000×)
对照组肺微血管内皮细胞及基底膜形态和结构正常；模型组肺微血管内皮细胞肿胀严重,基底膜缺损、模糊、疏松,肺毛细血管壁电子密度明显降低；低剂量组肺微血管内皮细胞轻度肿胀,基底膜较疏松,毛细血管壁电子密度大致正常；高剂量组肺微血管内皮细胞稍有肿胀,基底膜较完整,毛细血管壁电子密度大致正常。
9.肺泡Ⅱ型上皮细胞(ATⅡ)形态电镜结果(6000×)
对照组ATⅡ微绒毛排列整齐,呈细长指状突起,胞浆内有大量线粒体和板层小体,板层小体结构清晰,基膜完整；模型组ATⅡ微绒毛大片脱落,板层小体空泡化,微丝缩短变粗,模糊,断裂,线粒体空泡变性,基膜不完整；高剂量组ATⅡ微绒毛排列较整齐,线粒体及板层小体略有肿胀,基膜较完整；P2组ATⅡ微绒毛排列较整齐,线粒体及板层小体大致正常,微丝清晰,基膜较完整。
第三部分：
1.各组间性别、年龄、体重、手术时间、转流时间、主动脉阻断时间、心脏复跳情况,术后随访患儿机械通气及ICU停留时间差异无统计学意义(P>0.05)。
2.肺顺应性(Cd)：与基础值比较,常规组在各时间点升高(P<0.05)；与常规组比较,PHC低剂量和高剂量组转流前、主动脉开放后、停机时降低(P<0.05)。
3.呼吸指数(RI)：与基础值比较,常规组各时间点升高(P<0.05)；与常规组比较,PHC低剂量和高剂量组在气管插管后、转流前、主动脉开放后、停机时点降低(P<0.05)。
4.氧合指数(OI)：与基础值比较,常规组在各时间点降低(P<0.05)；与常规组比较,PHC低剂量和高剂量组在气管插管后、转流前、主动脉开放后、停机时点升高(P<0.05)。
5.气道峰压(Pmax):与基础值比较,常规组在各时间点升高(P<0.05)；与常规组比较,PHC低剂量和高剂量组在转流前、主动脉开放后、停机时点降低(P<0.05)。
6.TNF-α：与基础值比较,常规组在各时间点升高；与常规组比较,PHC低剂量和高剂量组转流前、主动脉开放后、停机时点降低(P<0.05)。
7. IL-6：与基础值比较,常规组在各时间点升高；与常规组比较,PHC低剂量和高剂量组转流前、主动脉开放后、停机时点降低(P<0.05)
8.血流动力学：
HR：与基础值比较,三组患儿HR在气管插管后1min升高(P<0.05)。常规组在切皮后1 min、劈胸骨后1min增加(P<0.05)。与常规组比较,PHC低剂量和高剂量组切皮后1 min、劈胸骨后1min下降(P<0.05)。
MAP：与基础值比较,三组患儿MAP在气管插管前下降(P<0.05)。常规组在切皮后1 min、劈胸骨后1min增加(P<0.05)。与常规组比较,PHC低剂量和高剂量组切皮后1 min、劈胸骨后1min下降(P<0.05)。
9.应激反应：
9.1皮质醇：与基础值比较,三组患儿在转流即刻、主动脉开放后2h、主动脉开放后24h升高(P<0.05)。与常规组比较,PHC低剂量和高剂量组在转流即刻、主动脉开放后2h、主动脉开放后24h降低(P<0.05)。
9.2乳酸：与基础值比较,三组患儿在主动脉开放即刻、主动脉开放后2h、主动脉开放后24h升高(P<0.05)。与常规组比较,PHC低剂量和高剂量组在主动脉开放即刻、主动脉开放后2h、主动脉开放后24h降低(P<0.05)。
9.3血糖：与基础值比较,三组患儿在主动脉开放即刻、主动脉开放后2h、主动脉开放后24h升高(P<0.05)。与常规组比较,PHC低剂量和高剂量组在主动脉开放即刻、主动脉开放后2h、主动脉开放后24h降低(P<0.05)。
10.肌钙蛋白(cTn-工)：与基础值比较,三组患儿在转流即刻、主动脉开放即刻、主动脉开放后2h、主动脉开放后24h升高(P<0.05)；与常规组比较,PHC低剂量和高剂量组在转流即刻、主动脉开放即刻、主动脉开放后2h、主动脉开放后24h降低(P＜0.05)。
11.乳酸脱氢酶(CK-MB):与基础值比较,三组患儿在转流即刻、主动脉开放即刻、主动脉开放后2h、主动脉开放后24h升高(P＜0.05)；与常规组比较,PHC低剂量和高剂量组在转流即刻、主动脉开放即刻、主动脉开放后2h、主动脉开放后24h降低(P＜0.05)。
结论：
1. PHC 0.04mg/kg应用于小儿腹部手术麻醉前用药,能够有效抑制唾液腺分泌,维持体温和血流动力学稳定,为PHC 0.04mg/kg广泛应用于小儿心内直视手术麻醉前用药提供依据,同时为PHC预处理应用于内毒素诱导大鼠ALI模型治疗和婴幼儿心内直视手术呼吸循环保护提供实验和理论依据。
2.建立了内毒素诱导大鼠ALI模型,静脉注射PHC0.25mg/kg和0.75mg/kg均能有效减轻脓毒症大鼠肺组织炎性反应,并且在一定剂量范围内呈剂量效应关系。
3.婴幼儿CPB前应用PHC 0.04mg/kg能有效抑制细胞因子TNF-α和IL-6,增加肺动态顺应性和氧合指数,减低呼吸指数和气道峰压,血流动力学平稳,抑制应激反应,改善微循环,降低受损心肌细胞CK-MB和cTn-Ⅰ,具有一定的呼吸循环保护作用。
4.减轻炎症反应是PHC预处理减轻婴幼儿CPB后呼吸、循环障碍的重要机制。PHC 0.04mg/kg和PHC 0.08mg/kg预处理应用于婴幼儿心内直视手术无剂量效应关系。
Background:The improvement of surgical treatment on children with congenital heart diseases (CHD) depend on identifying the patients who are prone to organ failure, regulating the risk factors in the preoperative and intraoperative period and effectively interfering about the organ protection during the pediatric open-heart surgery. Whether the children have respiratory and circulatory dysfunction after pediatric cardiopulmonary bypass (CPB) is the key factor leading to a successful pediatric open-heart surgery. How to prevent or mitigate the damages on the lung tissue and myocardium is a very important issue, which also is one of the greatest important problems that cardiac surgery, anesthesiology department, cardiopulmonary bypass department and even postoperative intensive care unit (ICU) care most. The drugs or other intervention perioperatively is significant for prevention and mitigation of respiratory and circulatory complications after CPB.
CPB is non-physiology situation. On the one hand it can cause permeability changes in the intestines, blood vessel and other tissues and organs, resulting in endotoxemia; on the other hand, blood, tubes and other CPB installations stimulate the body's inflammatory responses. Respiratory and circulatory systems are the most vulnerable to the impact.
It had been confirmed by a large number of in vitro an in vivo animal experiments and clinical studies that the belladonna drugs can improve microcirculation, protect cells and inhabit ischemia-reperfusion injuries. The cell protective effect of belladonna drugs may be related to blocking calcium influx and inhibiting membrane lipid peroxidation. It had been proved that anisodamine have a kind of protective effect on organs, but its side effects limit their clinical application. Penehyclidine hydrochloride (PHC) is a novel prolonged action cholinergic receptor blocker studied by China. The main mechanism is the selective interruption to the central and peripheral M1, M3 and N1, N2 receptors which have cell protective effects and can improve cell tolerance to hypoxia and ischemia, stabilize lysosomes and mitochondria and other sub-membrane structure inhibit the formation of arachidonic acid metabolites and shock factors, reduce the release of lysosomal enzymes and the permeability of capillary walls and the exudation of inflammatory factors, make central nervous system sedate lastingly and ameliorate the microcirculation. So it has been widely used in clinic. There are a few articles about protective effects of PHC on respiration and circulation and its mechanism. This study investigates the respiratory and circulatory protective effects and mechanism of PHC to the children after CPB. It can supply proper drugs, dosage and the theory to the protective effects of important organs on the children during the CPB. First, through the pretreatment of PHC in a large number of pediatric abdominal surgeries, present study observes the effect of different doses of PHC during anesthesia in abdominal surgery compared with the atropine group and lay the foundation for the PHC pretreatment to the rat model with the endotoxin-induced acute lung injury (ALI) and the pediatric open heart surgeries. Second, real-time-PCR (RT-PCR) technique was applied. The protective effects of PHC on rats with ALI provide the experimental and theoretical basis for respiratory protective effect of the pretreatment in the pediatric open heart surgeries. At last, present study takes PHC of 0.04mg/kg and the double dose as the premedication, observes the changes about cell factors, pulmonary respiratory function parameters, hemodynamics, stress response and myocardial injury and investigates the protective effects of different doses of PHC on infants after CPB.
Objective:Investigation of respiratory and circulatory protective effects of PHC on infants after CPB.
Materials and methods:
Part 1 Investigation of PHC as premedication in pediatric surgery
There are 1535 cases of pediatric abdominal surgeries (coming from pediatric surgery of the First Affiliated Hospital of Zhengzhou University from Jan,2008 to Dec,2009) which were divided in three groups randomly:P1 group:there were 608 cases of intravenous injection of PHC 0.02mg/kg; P2 group:729 cases of intravenous injection of PHC 0.04mg/kg; A group:198 cases of intravenous injection of atropine O.Olmg/kg; All the 1535 patients were injected in the peripheral vein by the experimental drugs and ketamine 2mg/kg 30 minutes after that in the induction room, then the children will be transferred into the operating room receiving the intravenous general anesthesia after lossing their consciousness. Present study observes the changes of the saliva secretion, temperature and blood flow dynamics in three groups.
Part 2 Investigation of effects of PHC on repair of acute 1 ung injury (ALI)
There are 48 cases healthy adult male SD rats which are divided into four groups randomly and there are 12 rats in each group:C group:tail vein injection of saline 1 ml/kg; M group:tail vein injection of E.coli Lipopolysacharide (LPS) 5mg/kg; P1: tail vein injection of E.coli LPS 5mg/kg and PHC 0.25mg/kg; P2:tail vein injection of E.coli LPS 5mg/kg and PHC 0.75mg/kg. In this part of experiment, animal study combined with RT-PCR technique was applied. Through establishment of endotoxin-induced rat model and comparison of controlled and model groups, present study investigate the plasma TNF-alpha and IL-6, PaO2 and PaCO2, water in lung tissue (WLT), water/dry (W/D) of lung tissue, gray scale rate of CD14 mRNA, pathology slides and electron microscope.
Part 3 This part is composed of the following two sections.
Section 1 Investigation of the respiratory protective effect of penehyclidine hydrochloride of infants after cardiopulmonary bypass
Section 2 Investigation of the circulatory protective effect of penehyclidine hydrochloride of infants after cardiopulmonary bypass
65 cases CHD surgeries (Department of Cardiac Surgery in the First Affiliated Hospital of Zhengzhou University) are divided into three groups randomly:P1 group: 25 cases are injected by PHC 0.04 mg·kg-1; P2 group:29 cases are injected by PHC 0.08 mg·kg-1; C group:11 cases are injected by the same volume saline at the same time which is slowly injected from the right internal jugular vein after the success of internal jugular vein puncture. Age range:8 months to 35 months. The male cases is 37 and female is 28 whose weight range is 6-16kg. There is no server pulmonary hypertension and disorder of hepatic function, renal function and coagulation in all children whose cardiac function is inⅡ～Ⅲgrade and ejection fraction (EF) is more than 60%. Collect the left radial artery blood 4 ml at each time point with heparin anticoagulation. One milliliter is used to monitor blood gas and the other three milliliters immediately centrifugate for 10 minutes at 4℃at 3000r/min. Then take the upper plasma to the -80℃refrigerator under test and record the peak airway pressure. Compared with the control group, this study investigate the effect of hemodynamics, Cd. RI,OI, Pmax, TNF-a,IL-6, cortisol, lactic acid, blood glucose, cTn-I,CK-MB in different doses of PHC groups.
The SPSS 17.0 statistical package is applied for statistical analysis to all data. The measurement data is showed in mean±standard deviation (x+s). The analysis of variance is used between groups. If the results are different, LSD will be used for pairwise comparison. Paired t test was applied to compare before and after CPB with count data usingχ2 test and ranked data using non-parametric test. The significant difference is a=0.05.
Conclusions:
Part 1
1. there is no significant difference among the groups of gender, age, weight, anesthesia time (from the time entering to the induction room to out of the recovery room),operative time and recovery time(from the end of surgery to the time out of the recovery room, p> 0.05).
2. The comparison of the saliva secretion:non-parametric test is used for comparison between groups and Mann-Whitney test is used for prirwise comparisons. It needed to calibrate because there are two comparisons between groups, a'=0.05/3=0.0167. There is significant difference of secretion during the endotracheal intubation (χ2=3342.76, P<0.01). There is significant difference between A group and P1 group(Z=46.26, P<0.01), and between the two PHC groups (Z=47.98,P<0.01) while there is no significant difference between A group and P2 group (Z=2.25, P=0.025>0.0167). while during the tracheal extubation, there is significant difference between groups(χ2=3607.57, P<0.01): A group and P1 group (Z=37.64, P<0.01), A group and P1 group (Z=52.12, P<0.01), P1 group and P2 group (Z= 47.07, P<0.01)
3. Temperature comparison:There is significant difference of body temperature among the three groups (x 2=3407.82, P<0.05). While there is no significant difference of basal body temperature (P>0.05). The temperature in atropine group increased 30 minutes after treatment (P<0.05). compared with A group, the temperature in the two PHC group decrease at T1 (P<0.05)
4. The comparison of heart rate (HR) and mean arterial blood pressure (MAP):
HR:there is significant difference of heart rate among the three groups (χ2=3278.17,P<0.05) and there is no significant difference of basal heart rate (P >0.05). As comparing with the basal heart rate, the HR increased at 5 minute,30 minute and 60 minute after treatment in the atropine group (P<0.01) and there is no difference in the PHC low-dose group and high-dose group (P>0.05).The HR in the two PHC groups decreased significantly compared with the atropine group (P>0.01). There is no significant difference between the two PHC groups (P>0.05).
MAP:there is no significant difference of mean arterial bood pressure (χ2=263.19, P>0.05).
Part 2
1. Plasma TNF-alpha:Compared with controlled group, plasma TNF-alpha among model group, low-dose PHC group and high-dose PHC increased significantly (P<0.01). TNF-alpha in both low-dose and high-dose PHC group were higher than that in model group (P<0.01). Compared with low-dose group, TNF-alpha in high-dose group reduced significantly (P<0.01).
2. Plasma IL-6:Compared with controlled group, plasma IL-6 among model group, low-dose PHC group and high-dose PHC increased significantly (P<0.01). IL-6 in both low-dose and high-dose PHC group were higher than that in model group (P<0.01). Compared with low-dose group, IL-6 in high-dose group reduced significantly (P<0.01).
3. PaO2 and PaCO2
In comparison with PaO2 in controlled group, it was declined significantly in model, low-dose PHC and high-dose PHC group (P<0.01). Level of PaO2 in low-dose and high-dose was raised significantly than that in model group (P<0.01) while there was no significant difference between the two PHC groups (P>0.05).
Compared with controlled group, PaCO2 in model group augmented significantly (P<0.01). PaCO2 in model group was higher than that in both PHC groups (P<0.05).
4. Water in Lung Tissue (WLT)
Compared with controlled group, WLT in model and both PHC groups was higher. In comparison with model group, WLT in both PHC groups was trimmed down (P<0.05). There was no significant difference of WLT between the two PHC groups (P>0.05).
5. Water/Dry (W/D) of Lung Tissue
In comparison with controlled group, rate of W/D in model and both PHC groups elevated significantly (P<0.05). Compared with model group, rate of W/D in both PHC groups was down significantly (P<0.05).
6. Gray Scale Rate (A value) of CD14 mRNA
In comparison with controlled group, A value in model and both PHC groups elevated significantly (P<0.05). Compared with model group, A value in both PHC groups was down significantly (P<0.05).
7. Pathology Slides(200×)
Pathology slides from controlled group demonstrated normal rat lung tissue with clear structure, thin alveolar wall and no infiltration of inflammatory cells between alveolar wall and interstitial substance. These from model group showed severe edema of lung tissue, hemorrhage, increased interstitial space, and significant collapse of alveoli, spreading of a great amount of red cells in interstitial and alveolar space, filtration of inflammatory cells and destroy of integrity of part of pulmonary alveoli. These from low-dose PHC group displayed mild edema of lung tissue, less amount of infiltrated inflammatory cells, reduced thickening of interstitial and collapse of alveoli with relative intact of structure of alveoli. Compared with pathology slides from low-dose PHC group, these form high-dose PHC group exhibited mild pulmonary edema, less infiltration of inflammatory cells and decreased injury of lung tissue with intact alveolar structure.
8. Morphology of pulmonary capillary endothelium and basement membrane under electron microscope (6000 X)
Structure of pulmonary capillary endothelium and basement membrane under electron microscope in controlled group was normal. In model group, pulmonary capillary endothelia had severe swollen; basement membrane revealed defect, loose and vague; and electronic density of capillary wall exhibited reduction. In both low-dose and high-dose PHC group, pulmonary capillary endothelia had mild edema with relatively normal morphology, less loosen basement membrane, and nearly normal electronic density of capillary wall.
9. Morphology of alveolar typeⅡepithelial cells (ATⅡ) under electron microscope(6000 X)
Morphology of ATⅡunder electron microscope in controlled group showed that microvilli lined up in good order with slim finger-like projections. There were a lot of lamellar bodies with clear structure and mitochondria in cytoplasm. Basement membrane was intact. In model group, microvilli shed severely with vacuolization of lamellar bodies, blurred, ruptured and shortened microfilament, vacuolar degeneration of mitochondria and damage of basement membrane. In low-dose group, microvilli lined up in good order with mild swollen mitochondria. Microfilament was clearly visible and basement membrane was relatively intact. In high-dose group, the order of microvilli was neat with normal morphologic lamellar bodies and mitochondria, clear microfilament and relatively intact basement membrane.
Part 3
1. There is no significant difference of gender, age, weight, operative time, bypass time, aortic cross-clamp time, cardiac resuscitation situation, mechanical ventilation of postoperative children followed up and the resistance time in ICU (P>0.05).
2. Dynamic Lung Compliance (Cd):compared with the basal point, the Cd in the control group is higher at any point (P<0.05), and that in PHC low-dose group and high-dose group increased before bypass, after aortic opening and the outage time (P<0.05).
3. Respiratory index (RI):the RI in the control group increased comparing with the basal point (P<0.05); and that increased in the two PHC groups after intubation, before bypass, aortic opening up and the outage time (P<0.05).
4. oxygenation index(OI):in comparison with the basal point the 01 in the control group increased (P<0.05); and it increased after intubation, before bypass, aortic opening up and the outage point in the PHC low-dose group and high-dose group (P<0.05).
5. Peak airway (Pmax):compared with the basal point, the Pmax in the control group decreased (P<0.05); and it decreased before bypass, aortic opening up and outage point in the PHC low-dose group and high-dose group (P<0.05).
6. TNF-a:in comparison with the basal value, the plasma TNF-alpha the control group increased (P<0.05); and it decreased before bypass, aortic opening up and the outage point in the PHC low-dose group and high-dose group (P<0.05).
7. IL-6:compared with the basal value, IL-6 in the control group increased (P<0.05); and it decreased at the time of before bypass, aortic opening up and stopping point in the two PHC groups (P<0.05).
8. Hemodynamics:
HR:As compared with the basal point, the HR in three groups increased at 1 minute after intubation (P<0.05), and that in control group increased at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).while HR decreased in the PHC low-dose group and high-dose group at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).
MAP:In comparison with the basal value, the MAP decreased before intubation in three groups(P<0.05), while that in control group increased at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).The MAP in the two PHC groups decreased at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).
9. Stress reaction:
9.1 Cortisol:Compared with the basal point, the cortisol in the three groups increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.05).In companion with the control group, that in the PHC low-dose group and high-dose group decreased at the time of bypass beginning,2 hours after aortic opening (P<0.05) and 24 hours after the opening (P<0.01).
9.2 lactic acid:Compared with the basal point, the lactic acid increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening in the three groups (P<0.05). As comparing with the control group, the lactic acid in the PHC low-dose group and high-dose group decreased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.05).
9.3 blood glucose:Compared with the base line, the blood glucose in the three groups increased at the time of aortic opening,2 hours after aortic opening and 24 hours after the opening (P<0.05). In comparison with the control group, the blood glucose in the two PHC grous decreased at the time of aortic opening,2 hours after aortic opening and 24 hours after the opening (P<0.05).
10. cardiac troponin (cTn-I):Compared with the base line, the cTn-I increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening in the three groups (P<0.01). As comparing with the control group, that in the PHC low-dose group and high-dose group decreased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.01).
11. MB isoenzyme of creatine kinase (CK-MB):Compared to the base line, the CK-MB increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening in the three groups (P<0.01). While compared with the control group, the CK-MB in the two PHC groups decreased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.01).
Conclusions:
1. PHC 0.04mg/kg is used in the pediatric abdominal surgeries as premedication. It can effectively inhibit the salivary gland secretion, maintain a stable temperature and hemodynamics, which lay the foundation for its widely use in pediatric open heart surgery and provide the experimental and theoretical basis for respiratory protective effect of the PHC to the rat model with the endotoxin-induced acute lung injury (ALI) and the pediatric open heart surgeries.
2. The endotoxin-induced rat model had been established. The intravenous injection of PHC 0.25mg/kg and 0.75mg/kg can effectively reduce the inflammatory response in septic rats with ALI and showed a definite dose-effect relationship.
3. The application of PHC 0.04mg/kg before CPB can effectively inhibit the release of TNF-α、IL-6, increase the dynamic pulmonary compliance and oxygenation index, reduce the respiratory index and the peak airway pressure, stable hemodynamic changes, inhibit stress response, improve microcirculation and reduce cTn-I and CK-MB of the damaged heart cells. So it has a certain kind of respiratory and circulatory protection.
4. It is an important mechanism of PHC as pretreatment that reduces the respiratory and circulatory disorder after CPB. There is no dose-effect relationship between the PHC 0.04mg/kg and PHC 0.08mg/kg in the pediatric open heart surgery.
CPB是把双刃剑,一方面可以帮助外科医生完成心脏外科手术,另一方面由于CPB中低温、血液稀释、非搏动灌注等非生理因素的影响,血液与异物表面接触,激活凝血系统、纤溶系统和白细胞,从而导致肠道、血管等组织器官通透性改变,产生内毒素血症和机体发生炎性反应。其中呼吸、循环是最易受累的重要系统。
大量离体和在体动物实验及临床研究都证实莨菪类药物具有改善微循环,细胞保护和抗再灌注损伤等作用。莨菪类药物的细胞保护作用,可能与阻断钙离子内流,抑制细胞膜的脂质过氧化有关。研究证实山莨菪碱有一定的器官保护作用,但因山莨菪碱副作用大,限制了其在临床的应用。盐酸戊乙奎醚(penehyclidine hydrochloride, PHC)是我国自主研究的新型长效胆碱能受体阻滞药。主要作用机制为选择性阻断中枢和外周的M1、M3和N1、N2受体,具有细胞保护作用,提高细胞对缺血缺氧的耐受性,稳定溶酶体和线粒体等亚细胞膜结构,减少溶酶体酶的释放,抑制花生四烯酸代谢产物的产生和休克因子的形成,减少毛细血管壁的通透性,减少炎性因子的渗出,持久的中枢镇静以及改善微循环的作用。已经广泛应用于临床。目前PHC对小儿CPB后呼吸、循环保护作用及机制相关报道甚少,本研究对比观察PHC预处理是否对婴幼儿CPB后呼吸循环功能具有保护作用及可能的作用机制,为临床婴幼儿CPB后重要脏器保护提供合适药物、剂量及理论依据。首先通过PHC应用于大样本小儿腹部手术麻醉前用药,观察与阿托品比较,不同剂量PHC在小儿腹部外科手术麻醉过程中的作用,为PHC预处理应用于内毒素诱导大鼠急性肺损伤模型和婴幼儿心内直视手术剂量选择提供依据；应用RT-PCR等技术对比观察PHC对内毒素诱导大鼠急性肺损伤的肺保护作用,为PHC预处理应用于婴幼儿心内直视手术呼吸功能保护提供实验和理论依据；最后选择不同剂量PHC预处理,观察婴幼儿CHD CPB后细胞因子、肺呼吸功能参数、血流动力学、应激反应和心肌损伤的变化,探讨PHC预处理对婴幼儿CPB后呼吸循环保护作用。
研究目的：探讨盐酸戊乙奎醚预处理对婴幼儿体外循环后呼吸循环保护作用。
材料与方法：
第一部分盐酸戊乙奎醚应用于小儿外科麻醉前用药临床研究
1535例小儿腹部手术(2008年1月～2009年12月,郑州大学第一附属医院小儿外科),随机分为三组：A组：静脉注射阿托品0.01mg/kg198例；P1组：静脉注射PHC0.02mg/kg608例；P2组：静脉注射PHC0.04mg/kg729例。所有小儿入诱导间外周静脉注射试验药物,30分钟后静脉注射氯胺酮2mg/kg,待患儿入睡后转入手术间,静脉复合全身麻醉,对比观察三组麻醉前用药唾液分泌量、体温和血流动力学变化。
第二部分盐酸戊乙奎醚对大鼠急性肺损伤修复的实验研究
48例清洁级健康成年雄性SD大鼠(郑州大学实验动物中心),随机分为4组：C组：尾静脉注射生理盐水1 ml/kg;M组：尾静脉注射大肠杆菌脂多糖(Lipopolysacharide,LPS)5mg/kg; P1组：尾静脉注射大肠杆菌LPS5mg/kg+PHC 0.25mg/kg;P2组：尾静脉注射大肠杆菌LPS5mg/kg+PHC0.75mg/kgo每组12只。将RT-PCR等方法应用于动物实验,建立内毒素诱导大鼠ALI模型,与对照组和模型组比较,观察血浆TNF-a和IL-6、血气、肺含水量、湿／干重比值(W/D)、CD14mRNA灰度比值、光镜和电镜结果。
第三部分本部分共分为两节
第一节盐酸戊乙奎醚预处理对婴幼儿体外循环后呼吸功能保护研究
第二节盐酸戊乙奎醚预处理对婴幼儿体外循环后循环功能保护研究
65例CHD手术(郑州大学第一附属医院心脏外科),随机分为三组：P1组：静脉注射PHC0.04mg·kg-125例；P2组：静脉注射PHC0.08mg·kg-129例；C组：同一时点静脉注射等容量生理盐水11例。颈内静脉穿刺成功后自右颈内静脉缓慢注入。年龄范围：8月～35月。男37例,女28例。体重6-16kg。所有患儿心功能Ⅱ-Ⅲ级,术前无肝肾功能及凝血功能异常,无肺动脉重度高压。射血分数(EF)≥60mmHg。各时点抽取左侧桡动脉血4ml,肝素抗凝。lml用于监测血气分析,3ml立即在4℃下以3000r/min离心10min,取上层血浆,置入-80℃冰箱内保存待测。各时点记录气道峰压。与常规组比较,观察不同剂量PHC血流动力学、Cd、RI、OI、Pmax、TNF-α、IL-6皮质醇、乳酸、血糖、cTn-Ⅰ、CK-MB结果。
所有数据应用SPSS17.0统计软件包进行统计学处理,计量资料以均数±标准差(x±s)表示,组内及组间比较采用方差分析,结果有差异后,采用LSD法进行两两比较,CPB前后比较采用配对t检验,计数资料采用x2检验,等级资料比较采用非参数检验,以a=0.05为显著性检验水准。
结果：
第一部分：
1.各组间性别、年龄、体重、麻醉时间(入诱导间至出苏醒室时间)、手术时间和苏醒时间(手术结束至出苏醒室时间)差异无统计学意义(P>0.05)。
2.唾液分泌物量的分级构成比较：采用非参数检验进行组间比较,两两比较采用Mann-Whitney检验,由于组间要进行3次两两比较,故对α进行校正,α'=0.05/3=0.0167。气管插管时,各组分泌物量差异有统计学意义(x 2=3342.76,P<0.01),A组和P1组比较有差异(Z=46.26,P<0.01),A组和P2组比较无差异(Z=2.25,P=-0.025>0.0167),P1组与P2组之间有统计学意义(Z=47.98,P<0.01)；气管拔管时,组间有统计学意义(x 2=3607.57,P<0.01),A组和P1组比较有差异(Z=37.64,P<0.01),A组和P2组比较有差异(Z=52.12,P<0.01),P1组与P2组之间有统计学意义(Z=47.07,P<0.01)。
3.体温比较：三组体温差异有统计学意义(x2=3407.82,P<0.05),基础体温差异无统计学意义(P＞0.05),组内比较,阿托品组在用药后30min升高,(P<0.05)。与A组比较,P1组、P2组在T1时点降低(P<0.05)
4.心率(HR)、平均动脉压(MAP)比较：
HR：三组HR差异有统计学意义(x 2=3278.17,P<0.05),基础HR差异无统计学意义(P>0.05)。与基础HR比较,阿托品组在用药后5 min,30min,60min明显上升(P<0.01)；PHC低剂量和高剂量组比较无差异(P＞0.05)。与阿托品组比较,PHC低剂量和高剂量组在用药后5 min,30min,60min明显下降(P<0.01)。PHC低剂量和高剂量组比较无差异(P>0.05)。
MAP：三组MAP比较无差异(x 2=263.19,P>0.05)。
第二部分：
1.四组血浆TNF-α比较：与对照组比较,模型组、PHC低剂量和高剂量组显著升高(P<0.01)；与模型组比较,PHC低剂量和高剂量组显著降低(P<0.01)；与低剂量组比较,高剂量组降低(P<0.05)。
2.四组血浆IL-6比较：与对照组比较,模型组、PHC低剂量和高剂量组显著升高(P<0.01)；与模型组比较,PHC低剂量和高剂量组显著降低(P<0.01)；与低剂量组比较,高剂量组降低(P<0.05)。
3.四组PaO2、PaCO2比较：
PaO2与对照组比较,模型组、PHC低剂量和高剂量组显著降低(P<0.01)；与模型组比较,PHC低剂量和高剂量组显著升高(P<0.01)；与低剂量组比较,高剂量组无差异(P>0.05)。
PaCO2与对照组比较,模型组升高(P<0.01)；与模型组比较,PHC低剂量和高剂量组降低(P<0.05),与低剂量组比较,高剂量组无差异(P>0.05)。
4.四组大鼠肺含水量比较：与对照组比较,模型组、PHC低剂量和高剂量组升高(P<0.05)；与模型组比较,PHC低剂量和高剂量组降低(P<0.05)；与低剂量组比较,高剂量组无差异(P>0.05)。
5.四组湿/干重比值(W/D)比较：与对照组比较,模型组、PHC低剂量和高剂量组升高(P<0.05)；与模型组比较,PHC低剂量和高剂量组降低(P<0.05)；与低剂量组比较,高剂量组无差异(P>0.05)。
6.四组大鼠CD14mRNA灰度比值(A值)：与正常对照组比较,模型组、低剂量组和高剂量组升高(P<0.05)；与模型组组比较,低剂量组和高剂量组降低(P<0.05),与低剂量组比较,高剂量组降低(P<0.05)。
7.肺组织病理改变光镜结果(200×)
对照组为正常大鼠肺组织,肺泡结构清晰,肺泡壁薄,未见炎性细胞浸润；模型组肺组织高度水肿、出血,肺间质增宽,肺泡腔和肺间质内可见大量红细胞,肺泡明显萎陷,炎症细胞大量浸润,肺泡完整性破坏；低剂量组肺组织水肿,肺间质增宽不明显,肺泡萎陷减轻,少量炎性细胞浸润,肺泡结构较完整；高剂量组肺组织轻度水肿,见炎性细胞浸润,肺泡结构完整。
8.肺微血管内皮细胞及基底膜形态电镜结果(6000×)
对照组肺微血管内皮细胞及基底膜形态和结构正常；模型组肺微血管内皮细胞肿胀严重,基底膜缺损、模糊、疏松,肺毛细血管壁电子密度明显降低；低剂量组肺微血管内皮细胞轻度肿胀,基底膜较疏松,毛细血管壁电子密度大致正常；高剂量组肺微血管内皮细胞稍有肿胀,基底膜较完整,毛细血管壁电子密度大致正常。
9.肺泡Ⅱ型上皮细胞(ATⅡ)形态电镜结果(6000×)
对照组ATⅡ微绒毛排列整齐,呈细长指状突起,胞浆内有大量线粒体和板层小体,板层小体结构清晰,基膜完整；模型组ATⅡ微绒毛大片脱落,板层小体空泡化,微丝缩短变粗,模糊,断裂,线粒体空泡变性,基膜不完整；高剂量组ATⅡ微绒毛排列较整齐,线粒体及板层小体略有肿胀,基膜较完整；P2组ATⅡ微绒毛排列较整齐,线粒体及板层小体大致正常,微丝清晰,基膜较完整。
第三部分：
1.各组间性别、年龄、体重、手术时间、转流时间、主动脉阻断时间、心脏复跳情况,术后随访患儿机械通气及ICU停留时间差异无统计学意义(P>0.05)。
2.肺顺应性(Cd)：与基础值比较,常规组在各时间点升高(P<0.05)；与常规组比较,PHC低剂量和高剂量组转流前、主动脉开放后、停机时降低(P<0.05)。
3.呼吸指数(RI)：与基础值比较,常规组各时间点升高(P<0.05)；与常规组比较,PHC低剂量和高剂量组在气管插管后、转流前、主动脉开放后、停机时点降低(P<0.05)。
4.氧合指数(OI)：与基础值比较,常规组在各时间点降低(P<0.05)；与常规组比较,PHC低剂量和高剂量组在气管插管后、转流前、主动脉开放后、停机时点升高(P<0.05)。
5.气道峰压(Pmax):与基础值比较,常规组在各时间点升高(P<0.05)；与常规组比较,PHC低剂量和高剂量组在转流前、主动脉开放后、停机时点降低(P<0.05)。
6.TNF-α：与基础值比较,常规组在各时间点升高；与常规组比较,PHC低剂量和高剂量组转流前、主动脉开放后、停机时点降低(P<0.05)。
7. IL-6：与基础值比较,常规组在各时间点升高；与常规组比较,PHC低剂量和高剂量组转流前、主动脉开放后、停机时点降低(P<0.05)
8.血流动力学：
HR：与基础值比较,三组患儿HR在气管插管后1min升高(P<0.05)。常规组在切皮后1 min、劈胸骨后1min增加(P<0.05)。与常规组比较,PHC低剂量和高剂量组切皮后1 min、劈胸骨后1min下降(P<0.05)。
MAP：与基础值比较,三组患儿MAP在气管插管前下降(P<0.05)。常规组在切皮后1 min、劈胸骨后1min增加(P<0.05)。与常规组比较,PHC低剂量和高剂量组切皮后1 min、劈胸骨后1min下降(P<0.05)。
9.应激反应：
9.1皮质醇：与基础值比较,三组患儿在转流即刻、主动脉开放后2h、主动脉开放后24h升高(P<0.05)。与常规组比较,PHC低剂量和高剂量组在转流即刻、主动脉开放后2h、主动脉开放后24h降低(P<0.05)。
9.2乳酸：与基础值比较,三组患儿在主动脉开放即刻、主动脉开放后2h、主动脉开放后24h升高(P<0.05)。与常规组比较,PHC低剂量和高剂量组在主动脉开放即刻、主动脉开放后2h、主动脉开放后24h降低(P<0.05)。
9.3血糖：与基础值比较,三组患儿在主动脉开放即刻、主动脉开放后2h、主动脉开放后24h升高(P<0.05)。与常规组比较,PHC低剂量和高剂量组在主动脉开放即刻、主动脉开放后2h、主动脉开放后24h降低(P<0.05)。
10.肌钙蛋白(cTn-工)：与基础值比较,三组患儿在转流即刻、主动脉开放即刻、主动脉开放后2h、主动脉开放后24h升高(P<0.05)；与常规组比较,PHC低剂量和高剂量组在转流即刻、主动脉开放即刻、主动脉开放后2h、主动脉开放后24h降低(P＜0.05)。
11.乳酸脱氢酶(CK-MB):与基础值比较,三组患儿在转流即刻、主动脉开放即刻、主动脉开放后2h、主动脉开放后24h升高(P＜0.05)；与常规组比较,PHC低剂量和高剂量组在转流即刻、主动脉开放即刻、主动脉开放后2h、主动脉开放后24h降低(P＜0.05)。
结论：
1. PHC 0.04mg/kg应用于小儿腹部手术麻醉前用药,能够有效抑制唾液腺分泌,维持体温和血流动力学稳定,为PHC 0.04mg/kg广泛应用于小儿心内直视手术麻醉前用药提供依据,同时为PHC预处理应用于内毒素诱导大鼠ALI模型治疗和婴幼儿心内直视手术呼吸循环保护提供实验和理论依据。
2.建立了内毒素诱导大鼠ALI模型,静脉注射PHC0.25mg/kg和0.75mg/kg均能有效减轻脓毒症大鼠肺组织炎性反应,并且在一定剂量范围内呈剂量效应关系。
3.婴幼儿CPB前应用PHC 0.04mg/kg能有效抑制细胞因子TNF-α和IL-6,增加肺动态顺应性和氧合指数,减低呼吸指数和气道峰压,血流动力学平稳,抑制应激反应,改善微循环,降低受损心肌细胞CK-MB和cTn-Ⅰ,具有一定的呼吸循环保护作用。
4.减轻炎症反应是PHC预处理减轻婴幼儿CPB后呼吸、循环障碍的重要机制。PHC 0.04mg/kg和PHC 0.08mg/kg预处理应用于婴幼儿心内直视手术无剂量效应关系。
Background:The improvement of surgical treatment on children with congenital heart diseases (CHD) depend on identifying the patients who are prone to organ failure, regulating the risk factors in the preoperative and intraoperative period and effectively interfering about the organ protection during the pediatric open-heart surgery. Whether the children have respiratory and circulatory dysfunction after pediatric cardiopulmonary bypass (CPB) is the key factor leading to a successful pediatric open-heart surgery. How to prevent or mitigate the damages on the lung tissue and myocardium is a very important issue, which also is one of the greatest important problems that cardiac surgery, anesthesiology department, cardiopulmonary bypass department and even postoperative intensive care unit (ICU) care most. The drugs or other intervention perioperatively is significant for prevention and mitigation of respiratory and circulatory complications after CPB.
CPB is non-physiology situation. On the one hand it can cause permeability changes in the intestines, blood vessel and other tissues and organs, resulting in endotoxemia; on the other hand, blood, tubes and other CPB installations stimulate the body's inflammatory responses. Respiratory and circulatory systems are the most vulnerable to the impact.
It had been confirmed by a large number of in vitro an in vivo animal experiments and clinical studies that the belladonna drugs can improve microcirculation, protect cells and inhabit ischemia-reperfusion injuries. The cell protective effect of belladonna drugs may be related to blocking calcium influx and inhibiting membrane lipid peroxidation. It had been proved that anisodamine have a kind of protective effect on organs, but its side effects limit their clinical application. Penehyclidine hydrochloride (PHC) is a novel prolonged action cholinergic receptor blocker studied by China. The main mechanism is the selective interruption to the central and peripheral M1, M3 and N1, N2 receptors which have cell protective effects and can improve cell tolerance to hypoxia and ischemia, stabilize lysosomes and mitochondria and other sub-membrane structure inhibit the formation of arachidonic acid metabolites and shock factors, reduce the release of lysosomal enzymes and the permeability of capillary walls and the exudation of inflammatory factors, make central nervous system sedate lastingly and ameliorate the microcirculation. So it has been widely used in clinic. There are a few articles about protective effects of PHC on respiration and circulation and its mechanism. This study investigates the respiratory and circulatory protective effects and mechanism of PHC to the children after CPB. It can supply proper drugs, dosage and the theory to the protective effects of important organs on the children during the CPB. First, through the pretreatment of PHC in a large number of pediatric abdominal surgeries, present study observes the effect of different doses of PHC during anesthesia in abdominal surgery compared with the atropine group and lay the foundation for the PHC pretreatment to the rat model with the endotoxin-induced acute lung injury (ALI) and the pediatric open heart surgeries. Second, real-time-PCR (RT-PCR) technique was applied. The protective effects of PHC on rats with ALI provide the experimental and theoretical basis for respiratory protective effect of the pretreatment in the pediatric open heart surgeries. At last, present study takes PHC of 0.04mg/kg and the double dose as the premedication, observes the changes about cell factors, pulmonary respiratory function parameters, hemodynamics, stress response and myocardial injury and investigates the protective effects of different doses of PHC on infants after CPB.
Objective:Investigation of respiratory and circulatory protective effects of PHC on infants after CPB.
Materials and methods:
Part 1 Investigation of PHC as premedication in pediatric surgery
There are 1535 cases of pediatric abdominal surgeries (coming from pediatric surgery of the First Affiliated Hospital of Zhengzhou University from Jan,2008 to Dec,2009) which were divided in three groups randomly:P1 group:there were 608 cases of intravenous injection of PHC 0.02mg/kg; P2 group:729 cases of intravenous injection of PHC 0.04mg/kg; A group:198 cases of intravenous injection of atropine O.Olmg/kg; All the 1535 patients were injected in the peripheral vein by the experimental drugs and ketamine 2mg/kg 30 minutes after that in the induction room, then the children will be transferred into the operating room receiving the intravenous general anesthesia after lossing their consciousness. Present study observes the changes of the saliva secretion, temperature and blood flow dynamics in three groups.
Part 2 Investigation of effects of PHC on repair of acute 1 ung injury (ALI)
There are 48 cases healthy adult male SD rats which are divided into four groups randomly and there are 12 rats in each group:C group:tail vein injection of saline 1 ml/kg; M group:tail vein injection of E.coli Lipopolysacharide (LPS) 5mg/kg; P1: tail vein injection of E.coli LPS 5mg/kg and PHC 0.25mg/kg; P2:tail vein injection of E.coli LPS 5mg/kg and PHC 0.75mg/kg. In this part of experiment, animal study combined with RT-PCR technique was applied. Through establishment of endotoxin-induced rat model and comparison of controlled and model groups, present study investigate the plasma TNF-alpha and IL-6, PaO2 and PaCO2, water in lung tissue (WLT), water/dry (W/D) of lung tissue, gray scale rate of CD14 mRNA, pathology slides and electron microscope.
Part 3 This part is composed of the following two sections.
Section 1 Investigation of the respiratory protective effect of penehyclidine hydrochloride of infants after cardiopulmonary bypass
Section 2 Investigation of the circulatory protective effect of penehyclidine hydrochloride of infants after cardiopulmonary bypass
65 cases CHD surgeries (Department of Cardiac Surgery in the First Affiliated Hospital of Zhengzhou University) are divided into three groups randomly:P1 group: 25 cases are injected by PHC 0.04 mg·kg-1; P2 group:29 cases are injected by PHC 0.08 mg·kg-1; C group:11 cases are injected by the same volume saline at the same time which is slowly injected from the right internal jugular vein after the success of internal jugular vein puncture. Age range:8 months to 35 months. The male cases is 37 and female is 28 whose weight range is 6-16kg. There is no server pulmonary hypertension and disorder of hepatic function, renal function and coagulation in all children whose cardiac function is inⅡ～Ⅲgrade and ejection fraction (EF) is more than 60%. Collect the left radial artery blood 4 ml at each time point with heparin anticoagulation. One milliliter is used to monitor blood gas and the other three milliliters immediately centrifugate for 10 minutes at 4℃at 3000r/min. Then take the upper plasma to the -80℃refrigerator under test and record the peak airway pressure. Compared with the control group, this study investigate the effect of hemodynamics, Cd. RI,OI, Pmax, TNF-a,IL-6, cortisol, lactic acid, blood glucose, cTn-I,CK-MB in different doses of PHC groups.
The SPSS 17.0 statistical package is applied for statistical analysis to all data. The measurement data is showed in mean±standard deviation (x+s). The analysis of variance is used between groups. If the results are different, LSD will be used for pairwise comparison. Paired t test was applied to compare before and after CPB with count data usingχ2 test and ranked data using non-parametric test. The significant difference is a=0.05.
Conclusions:
Part 1
1. there is no significant difference among the groups of gender, age, weight, anesthesia time (from the time entering to the induction room to out of the recovery room),operative time and recovery time(from the end of surgery to the time out of the recovery room, p> 0.05).
2. The comparison of the saliva secretion:non-parametric test is used for comparison between groups and Mann-Whitney test is used for prirwise comparisons. It needed to calibrate because there are two comparisons between groups, a'=0.05/3=0.0167. There is significant difference of secretion during the endotracheal intubation (χ2=3342.76, P<0.01). There is significant difference between A group and P1 group(Z=46.26, P<0.01), and between the two PHC groups (Z=47.98,P<0.01) while there is no significant difference between A group and P2 group (Z=2.25, P=0.025>0.0167). while during the tracheal extubation, there is significant difference between groups(χ2=3607.57, P<0.01): A group and P1 group (Z=37.64, P<0.01), A group and P1 group (Z=52.12, P<0.01), P1 group and P2 group (Z= 47.07, P<0.01)
3. Temperature comparison:There is significant difference of body temperature among the three groups (x 2=3407.82, P<0.05). While there is no significant difference of basal body temperature (P>0.05). The temperature in atropine group increased 30 minutes after treatment (P<0.05). compared with A group, the temperature in the two PHC group decrease at T1 (P<0.05)
4. The comparison of heart rate (HR) and mean arterial blood pressure (MAP):
HR:there is significant difference of heart rate among the three groups (χ2=3278.17,P<0.05) and there is no significant difference of basal heart rate (P >0.05). As comparing with the basal heart rate, the HR increased at 5 minute,30 minute and 60 minute after treatment in the atropine group (P<0.01) and there is no difference in the PHC low-dose group and high-dose group (P>0.05).The HR in the two PHC groups decreased significantly compared with the atropine group (P>0.01). There is no significant difference between the two PHC groups (P>0.05).
MAP:there is no significant difference of mean arterial bood pressure (χ2=263.19, P>0.05).
Part 2
1. Plasma TNF-alpha:Compared with controlled group, plasma TNF-alpha among model group, low-dose PHC group and high-dose PHC increased significantly (P<0.01). TNF-alpha in both low-dose and high-dose PHC group were higher than that in model group (P<0.01). Compared with low-dose group, TNF-alpha in high-dose group reduced significantly (P<0.01).
2. Plasma IL-6:Compared with controlled group, plasma IL-6 among model group, low-dose PHC group and high-dose PHC increased significantly (P<0.01). IL-6 in both low-dose and high-dose PHC group were higher than that in model group (P<0.01). Compared with low-dose group, IL-6 in high-dose group reduced significantly (P<0.01).
3. PaO2 and PaCO2
In comparison with PaO2 in controlled group, it was declined significantly in model, low-dose PHC and high-dose PHC group (P<0.01). Level of PaO2 in low-dose and high-dose was raised significantly than that in model group (P<0.01) while there was no significant difference between the two PHC groups (P>0.05).
Compared with controlled group, PaCO2 in model group augmented significantly (P<0.01). PaCO2 in model group was higher than that in both PHC groups (P<0.05).
4. Water in Lung Tissue (WLT)
Compared with controlled group, WLT in model and both PHC groups was higher. In comparison with model group, WLT in both PHC groups was trimmed down (P<0.05). There was no significant difference of WLT between the two PHC groups (P>0.05).
5. Water/Dry (W/D) of Lung Tissue
In comparison with controlled group, rate of W/D in model and both PHC groups elevated significantly (P<0.05). Compared with model group, rate of W/D in both PHC groups was down significantly (P<0.05).
6. Gray Scale Rate (A value) of CD14 mRNA
In comparison with controlled group, A value in model and both PHC groups elevated significantly (P<0.05). Compared with model group, A value in both PHC groups was down significantly (P<0.05).
7. Pathology Slides(200×)
Pathology slides from controlled group demonstrated normal rat lung tissue with clear structure, thin alveolar wall and no infiltration of inflammatory cells between alveolar wall and interstitial substance. These from model group showed severe edema of lung tissue, hemorrhage, increased interstitial space, and significant collapse of alveoli, spreading of a great amount of red cells in interstitial and alveolar space, filtration of inflammatory cells and destroy of integrity of part of pulmonary alveoli. These from low-dose PHC group displayed mild edema of lung tissue, less amount of infiltrated inflammatory cells, reduced thickening of interstitial and collapse of alveoli with relative intact of structure of alveoli. Compared with pathology slides from low-dose PHC group, these form high-dose PHC group exhibited mild pulmonary edema, less infiltration of inflammatory cells and decreased injury of lung tissue with intact alveolar structure.
8. Morphology of pulmonary capillary endothelium and basement membrane under electron microscope (6000 X)
Structure of pulmonary capillary endothelium and basement membrane under electron microscope in controlled group was normal. In model group, pulmonary capillary endothelia had severe swollen; basement membrane revealed defect, loose and vague; and electronic density of capillary wall exhibited reduction. In both low-dose and high-dose PHC group, pulmonary capillary endothelia had mild edema with relatively normal morphology, less loosen basement membrane, and nearly normal electronic density of capillary wall.
9. Morphology of alveolar typeⅡepithelial cells (ATⅡ) under electron microscope(6000 X)
Morphology of ATⅡunder electron microscope in controlled group showed that microvilli lined up in good order with slim finger-like projections. There were a lot of lamellar bodies with clear structure and mitochondria in cytoplasm. Basement membrane was intact. In model group, microvilli shed severely with vacuolization of lamellar bodies, blurred, ruptured and shortened microfilament, vacuolar degeneration of mitochondria and damage of basement membrane. In low-dose group, microvilli lined up in good order with mild swollen mitochondria. Microfilament was clearly visible and basement membrane was relatively intact. In high-dose group, the order of microvilli was neat with normal morphologic lamellar bodies and mitochondria, clear microfilament and relatively intact basement membrane.
Part 3
1. There is no significant difference of gender, age, weight, operative time, bypass time, aortic cross-clamp time, cardiac resuscitation situation, mechanical ventilation of postoperative children followed up and the resistance time in ICU (P>0.05).
2. Dynamic Lung Compliance (Cd):compared with the basal point, the Cd in the control group is higher at any point (P<0.05), and that in PHC low-dose group and high-dose group increased before bypass, after aortic opening and the outage time (P<0.05).
3. Respiratory index (RI):the RI in the control group increased comparing with the basal point (P<0.05); and that increased in the two PHC groups after intubation, before bypass, aortic opening up and the outage time (P<0.05).
4. oxygenation index(OI):in comparison with the basal point the 01 in the control group increased (P<0.05); and it increased after intubation, before bypass, aortic opening up and the outage point in the PHC low-dose group and high-dose group (P<0.05).
5. Peak airway (Pmax):compared with the basal point, the Pmax in the control group decreased (P<0.05); and it decreased before bypass, aortic opening up and outage point in the PHC low-dose group and high-dose group (P<0.05).
6. TNF-a:in comparison with the basal value, the plasma TNF-alpha the control group increased (P<0.05); and it decreased before bypass, aortic opening up and the outage point in the PHC low-dose group and high-dose group (P<0.05).
7. IL-6:compared with the basal value, IL-6 in the control group increased (P<0.05); and it decreased at the time of before bypass, aortic opening up and stopping point in the two PHC groups (P<0.05).
8. Hemodynamics:
HR:As compared with the basal point, the HR in three groups increased at 1 minute after intubation (P<0.05), and that in control group increased at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).while HR decreased in the PHC low-dose group and high-dose group at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).
MAP:In comparison with the basal value, the MAP decreased before intubation in three groups(P<0.05), while that in control group increased at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).The MAP in the two PHC groups decreased at 1 minute after skin incision and 1 minute after sternotomy (P<0.05).
9. Stress reaction:
9.1 Cortisol:Compared with the basal point, the cortisol in the three groups increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.05).In companion with the control group, that in the PHC low-dose group and high-dose group decreased at the time of bypass beginning,2 hours after aortic opening (P<0.05) and 24 hours after the opening (P<0.01).
9.2 lactic acid:Compared with the basal point, the lactic acid increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening in the three groups (P<0.05). As comparing with the control group, the lactic acid in the PHC low-dose group and high-dose group decreased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.05).
9.3 blood glucose:Compared with the base line, the blood glucose in the three groups increased at the time of aortic opening,2 hours after aortic opening and 24 hours after the opening (P<0.05). In comparison with the control group, the blood glucose in the two PHC grous decreased at the time of aortic opening,2 hours after aortic opening and 24 hours after the opening (P<0.05).
10. cardiac troponin (cTn-I):Compared with the base line, the cTn-I increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening in the three groups (P<0.01). As comparing with the control group, that in the PHC low-dose group and high-dose group decreased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.01).
11. MB isoenzyme of creatine kinase (CK-MB):Compared to the base line, the CK-MB increased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening in the three groups (P<0.01). While compared with the control group, the CK-MB in the two PHC groups decreased at the time of bypass beginning,2 hours after aortic opening and 24 hours after the opening (P<0.01).
Conclusions:
1. PHC 0.04mg/kg is used in the pediatric abdominal surgeries as premedication. It can effectively inhibit the salivary gland secretion, maintain a stable temperature and hemodynamics, which lay the foundation for its widely use in pediatric open heart surgery and provide the experimental and theoretical basis for respiratory protective effect of the PHC to the rat model with the endotoxin-induced acute lung injury (ALI) and the pediatric open heart surgeries.
2. The endotoxin-induced rat model had been established. The intravenous injection of PHC 0.25mg/kg and 0.75mg/kg can effectively reduce the inflammatory response in septic rats with ALI and showed a definite dose-effect relationship.
3. The application of PHC 0.04mg/kg before CPB can effectively inhibit the release of TNF-α、IL-6, increase the dynamic pulmonary compliance and oxygenation index, reduce the respiratory index and the peak airway pressure, stable hemodynamic changes, inhibit stress response, improve microcirculation and reduce cTn-I and CK-MB of the damaged heart cells. So it has a certain kind of respiratory and circulatory protection.
4. It is an important mechanism of PHC as pretreatment that reduces the respiratory and circulatory disorder after CPB. There is no dose-effect relationship between the PHC 0.04mg/kg and PHC 0.08mg/kg in the pediatric open heart surgery.
引文
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